The ultimate goal of this proposal is to develop a novel oncolytic virus to enhance therapy of brain tumors. OV treatment of tumors relies on cancer-specific replication of the virus leading to tumor destruction with minimal toxicity to adjacent non-neoplastic tissue. Results from the 5 clinical trials in patients with malignant glioma have shown the relative safety of this novel treatment modality. However evidence for significant efficacy remains to be established. Inefficient viral dispersal through the tumor interstitium can lead to poor viral spread hence not permitting efficient tumor cell infection and oncolysis. Efforts to increase viral spread within the tumor should lead to improved efficacy. We believe that glioma extracellular matrix (ECM) poses a significant barrier for efficient viral 'spread through the tumor, and hence limits its efficacy. In our preliminary experiments we have tested the effect of an ECM modulating enzyme on OV dispersal in glioma. The use of proteases to enhance viral spread has been tested and has shown efficacy in subcutaneous tumor models. However since the expression of proteases in the brain can result in toxicity related to hemorrhaging, they have not been tested for efficacy in intracranial gliomas. More recently co-administration of hyaluronidase with adenovirus has shown increased viral spread and therapeutic efficacy against subcutaneous tumors in mice. However the expression of hyaluronidase elicits astrocytic reactivity which limits its usage for intracranial gliomas. Here we propose to create a novel dually armed OV that can selectively infect and destroy glioma cells and also expresses a previously untested glioma ECM modulating enzyme to enhance viral spread. Previous studies have shown that even repeated injections of this purified enzyme within the rat brain resulted in no toxicity. We believe this study is highly significant as the use of such an ECM modulating enzyme to enhance OV spread and efficacy has not been previously tested. PUBLIC HEALTH RELEVANCE: The American Cancer Society predicts that there will be 12, 740 deaths due to cancers of the brain/nervous system. Despite decades of research prognosis for patients suffering from malignant gliomas remains poor. Oncolytic viral therapy is an experimental treatment which is currently being evaluated in clinical trials for efficacy against brain tumors. Inefficient viral spread through the tumor is thought to be one of the major impediments in the success of this therapy. The proposed research outlined in this grant is highly significant because it will result in the development of a novel dually armed OV that can selectively kill glioma cells and also secrete a glioma ECM modulating enzyme that will result in enhancement of this therapeutic modality. This will help translate oncolytic viral therapy into an efficacious treatment for tumors.